title: Fine mapping of Xq11.1-q21.33 and mutation screening of RPS6KA6, ZNF711, ACSL4, DLG3, and IL1RAPL2 for autism spectrum disorders (ASD).
abstract: About 80% of cases with autism express intellectual disability. Both in autism and in mental retardation without autism the majority of the cases are males, suggesting a X-chromosomal effect. In fact, some molecular evidence has been obtained for a common genetic background for autism spectrum disorders (ASD) and X-linked mental retardation (XLMR). In several genome-wide scans (GWS), evidence for linkage at X-chromosome has been reported including the GWS of Finnish ASD families with the highest multipoint lod score (MLS) of 2.75 obtained close to DXS7132 at Xq11.1. To further dissect the relationship between autism and genes implicated in XLMR, we have fine-mapped Xq11.1-q21.33 and analyzed five candidate genes in the region. We refined the region using 26 microsatellite markers and linkage analysis in 99 Finnish families with ASD. The most significant evidence for linkage was observed at DXS1225 on Xq21.1 with a nonparametric multipoint NPL(all) value of 3.43 (P = 0.0004). We sequenced the coding regions and splice sites of RPS6KA6 and ZNF711 residing at the peak region in 42 male patients from families contributing to the linkage. We also analyzed ACSL4 and DLG3, which have previously been known to cause XLMR and IL1RAPL2, a homologous gene for IL1RAPL1 that is mutated in autism and XLMR. A total of six novel and 11 known single nucleotide polymorphisms were identified. Further studies are warranted to analyze the candidate genes at Xq11.1-q21.33.
authors.affiliation: Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Katri
authors.initials: K
authors.lastname: Kantojärvi
authors.forename: Ilona
authors.initials: I
authors.lastname: Kotala
authors.forename: Karola
authors.initials: K
authors.lastname: Rehnström
authors.forename: Tero
authors.initials: T
authors.lastname: Ylisaukko-Oja
authors.forename: Raija
authors.initials: R
authors.lastname: Vanhala
authors.forename: Taina Nieminen
authors.initials: TN
authors.lastname: von Wendt
authors.forename: Lennart
authors.initials: L
authors.lastname: von Wendt
authors.forename: Irma
authors.initials: I
authors.lastname: Järvelä
mesh_terms: D000293:Adolescent; D000483:Alleles; D020817:Asperger Syndrome / Q000235:genetics; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D002675:Child, Preschool; D002874:Chromosome Mapping; D041321:Chromosomes, Human, X / Q000235:genetics*; D003066:Coenzyme A Ligases / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005387:Finland; D056726:Genetic Association Studies; D008040:Genetic Linkage; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007223:Infant; D053577:Interleukin-1 Receptor Accessory Protein / Q000235:genetics*; D008126:Lod Score; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics*; D012729:Sex Chromosome Aberrations; D014157:Transcription Factors / Q000235:genetics*; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: C116869:DLG3 protein, human; D004268:DNA-Binding Proteins; C407644:IL1RAPL2 protein, human; D053577:Interleukin-1 Receptor Accessory Protein; D009687:Nuclear Proteins; D014157:Transcription Factors; C484727:ZNF711 protein, human; C501305:RPS6KA6 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D003066:Coenzyme A Ligases; D000098859:Long-Chain-Fatty-Acid-CoA Ligase